واكسنهاي. PROCESS VALIDATION Of MULTIVALENT BACTERIAL VACCINES

Transcription

1 معتبرسازي فرايند واكسنهاي توليد باكتريايي چند گانه PROCESS VALIDATION Of MULTIVALENT BACTERIAL VACCINES ١

2 Program Overview Terms & Definitions Implementing a Validation Program Essential Requirements Matrix approaches to Process Validation A Case Study ٢

3 Why Validate? Required by: WHO and NRA FDA s QSR ISO ٣

4 REASONS FOR VALIDATION Customer satisfaction: Customer Mandated: Product liability: Reduced production costs: PV leads to reduced : inspections, testing, scrap and rework. Shifts costs from production to prevention. Supports improvements: the next generation of the process. Regulatory requirement ٤

5 CFR Title 21 Part a) Where the results a) cannot be fully verified b) shall be validated with a high degree of assurance and c) approved according to established procedures. d) The validation activities and results, shall be documented. b) shall establish and maintain procedures a) for monitoring and control of process parameters for validated processes b) to ensure that the specified requirements continue to be met. c) Qualified person are operating ٥

6 INTRODUCTION The goal of any Process Validation is to ensure process : CONSITENCY & ROBUSTNESS so that each lot of product is of same: PURITY, POTENCY and overall quality as: EVERY OTHER LOT ٦

7 Basic Principles process equipment : controlling, monitoring, and/or measuring equipment: replicate cycles (runs) demonstrate that the processes have been operated within the prescribed parameters for the process that the output or product consistently meets predetermined specifications for quality and function. Monitor the validated process during routine operation. As needed, requalify and recertify the equipment. ٧

8 Terms & Definitions Validation: Confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled Process validation: Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. ٨

9 Terms & Definitions Validation protocol: A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results (FDA Guidance). Verification: Confirmation by examination and provision of objective evidence that specified requirements have been fulfilled. ٩

10 WHEN SHOULD PROCESSES BE VALIDATED? Where process results cannot be fully verified during routine production by inspection and test, the process must be validated according to established procedures The following model may be useful in determining whether or not a process should validated: A Is Process Output Verifiable YES B Is V erification S ufficient & Cost Effective YES C Verify & Control the Process NO NO D Validate E Redesign Product and/or Process ١٠

11 WHEN SHOULD PROCESSES BE VALIDATED? Routine end-product tests have insufficient sensitivity verify the desired safety and efficacy of the finished devices. Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished product. The process capability is unknown, or it is suspected ١١

12 Relation of Risk Analysis For complex or critical processes, risk analysis is needed prior to establishing validation requirements. which output parameters should be concentrated assist in the development of appropriate tests. ١٢

13 Getting Started Develop a Validation Program that Defines: Responsibilities Process Type Definition Flow Chart With Decision Points Methods Forms Documentation ١٣

14 PROCESS VALIDATION MASTER PLAN Provides the roadmap for conducting validations. Establishes criticality of the process. Defines the validation approach. Provides documented evidence of the validation Establishes requirements for process changes. ١٤

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16 Process Type Four process types what qualifications are required when these qualifications must be completed. Verified fully verified by subsequent inspections or tests, does not have any equipment which require an Installation Qualification. No validation is required. Type I A process which is fully verified by subsequent inspections or tests, but relies on relevant equipment. An Installation Qualification and a Software Qualification (if applicable) are required prior to pilot or production use. ١٦

17 Process Type Type II A process the results of which cannot be fully verified by subsequent inspection and tests. Process validation must be completed prior to production use. Type III A Type II process that if not satisfactorily performed could result in serious injury to the patient. Examples are: o Sterilization o Aseptic Transfer o Performance tests o Blending / Mixing of critical solutions Note: Serious injury (1) is life threatening, (2) results in permanent impairment (3) necessitates medical or surgical intervention ١٧

18 Test Plans and Test Reports Test Plans are required to include: o Scope that includes the objectives of the test o Hypothesis/Expected Outcome o Sample requirements o Test methods or procedures o Requirements for test report o Reference Documents (if required) ١٨

19 The protocol plan must contain: Title - the process or item to be evaluated Purpose - the proposed change and the reason for making it. Scope - the range of products, processes, or equipment to which the protocol applies. Hypothesis / Expected Outcome - the criteria by which success will be judged. Reference Documents - Any procedures or test methods to be used, or other forms, diagrams, or relevant documents needed to conduct the protocol. Sample Requirements - A rationale for the number and type of parts to be tested. Test Description - The required test parameters, quantity, and frequency that will result in sufficient data for evaluation. Procedure - A step-by-step description of the work to be done. Disposition Of Parts both during and after the protocol Attachments - Any forms or relevant documents needed to conduct the protocol ١٩

20 The Protocol Report will include: Title - the process or item that was evaluated Purpose & Scope - as described above Reference Documents - only if not included in the Protocol Plan Results - The results of the testing, and identification of all tested product Discussion - The meaning of the test results as compared to the purpose Deviations & Additions - Identify all deviations and additions from the plan, with justification for the changes. Conclusion - A summary of the results and a statement as to the success or failure of the protocol. ٢٠

21 Revalidation All or a portion of a validation that is required to be repeated when changes that affect the original validation are made. Examples of changes requiring revalidation Changes to: product specifications Process parameters Equipment (type, function, location, control system, major repairs) Raw materials Manufacturing materials ٢١

22 Recurring Validation Recurring validation is all or a portion of a validation that is required to be repeated periodically, and demonstrates continuing compliance of a validated process or operation. Examples include sterilization and aseptic systems. ٢٢

23 Essential Requirements Industry generally satisfies by conducting: Installation Qualification Operational Qualification Performance Qualification ٢٣

24 Installation Qualification Studies which are conducted to show that all equipment relevant to the process: - was installed correctly - and is capable of meeting supplier s and/or manufacturer s specifications. ٢٤

25 Examples of IQ Elements (as appropriate) Installation conditions and check (utilities, wiring, etc.) Equipment documentation (drawings, schematics, spare parts list, manuals, etc.) software documentation Environmental conditions (such as clean room requirements, temperature, humidity) Preventative maintenance schedule Calibration requirements Identification of repair operations ٢٥

26 Operational Qualification Studies which are designed to - challenge the process and process equipment, - meets predetermined requirements throughout all anticipated operating ranges. ٢٦

27 Examples of OQ Elements (as appropriate) Verification of all systems and subsystem functions Confirmation of all safety devices and systems Software qualification worst-case testing Operator training and qualification ٢٧

28 Performance Qualification Studies conducted to demonstrate the process will consistently produce acceptable product - under normal operating conditions. - Challenges to the process should simulate actual manufacturing. ٢٨

29 Examples of PQ Elements (as appropriate) Verification of released process documentation (manufacturing procedures, inspection procedures, product specifications, engineering drawings, tool drawings, material specifications, related forms, etc.) Process stability (x-bar & R charts) Process capability (C p, C p k ) Fault seeding Cleanliness tests (extraction tests, ESCA, etc.) Biological tests (bioburden, cytotoxicity, hemolysis, etc.) Product sterility testing of Controlled Environments ٢٩

30 Measurement Qualification Repeatability & Reproducibility (R&R) An R&R must be conducted on measurement equipment to assure meaningful results. Repeatability Variation in measurements obtained with one gage when used several times by one operator while measuring a characteristic on one part. Reproducibility Variation in the average of the measurements made by different operators using the same gage when measuring a characteristic on one part. The R&R is then evaluated according to the following table: 0-10% Excellent 11-20% Adequate 21-30% Marginally Acceptable > 30% Unacceptable ٣٠

31 Worst Case Testing Worst case testing is the set of : conditions encompassing upper and lower processing limits and circumstances, which pose the greatest chance of failure. Example: In equipment cleaning: Post use hold time Cleaning agent exposure time Number of water rinse ٣١

32 Worst Case Testing FAULT SEED TESTING For inspection processes, documented evidence must be provided that the process is capable of rejecting product that does not meet specified requirements. Fault seed testing is conducted by randomly testing unacceptable product, and verifying the inspection process rejects this product. The inspector should not know which product is acceptable, and ideally should be unaware that the process is being tested. ٣٢

33 Matrix Approaches to Process Validation In multiple validation study : Example: 2 approach in cleaning condition of an equipment with different materials: 1) Validating one by one 2) Validating a representative The same as combination or multivalent vaccines : 1) different antigen as a product family 2) look for similarities 3) choose one representative for each group ٣٣

34 Case Study A 23-Valent POLYSACCHARIDE-BASED PNEUMOCCOCAL VACCINE : Pneumovax23 against adult Pneumococcal disease by Streptocccus pneumoniae. Consists of purified capsular polysaccharides from 23 most prevalent or invasive types. Manufactured by individually fermenting each serotype In a formal condition : 69 lots should be validated! ٣٤

35 Module Flow Diagram Goal Quality Management Fermentation Cell expansion Polysaccharide Biosynthesis Culture Identity and Purity Inactivation Inactivation Inactivating agent concentration Clarification Remove of Cell debris Turbidity after Clarification Membrane Ultrafiltration Volume reduction Remove Nucleic Acid Nucleic Acid level Polishing Remove Protein Remove Cell debris Protein level Tubidity Product Recovery Recover Product, Remove Solvent Product Yeild Release Test ٣٥

36 Critical Process Parameters (CPP) Critical Quality Attributes (CQA) ٣٦

37 Membrane Ultrafiltration Modules The goal : Reduce the volume of the Clarified fermentation broth. 2 membrane molecular weight cutoffs : 15 serotypes use 100-kDa MWCO 8 serotypes use 500-kDa MWCO Process Consistency can shown ٣٧

38 FDA References Quality System Regulation, Title 21 Part 820 of the Code of Federal Regulations( cfr/cfrsearch.cfm? CFRPart=820, Apr 2003) Medical Device Quality Systems Manual: A Small Entity Compliance Guide ( Dec 1996) Guideline on General Principles of Process Validation ( May 1987) Guide to Inspections of Medical Device Manufacturers ( ml, Dec 1997) ٣٨

39 Non-FDA References Process Validation in Manufacturing of biopharmaceuticals by : Gail Sofer 2005 ISO Quality Systems - Model for quality assurance in design, development, production, installation and servicing EN Application of EN ISO 9001 to the manufacture of medical devices GHTF/SG3/N99-10:2004 (Edition 2), Process Validation Guidance ( Jan 2004) ٣٩

40 QUESTIONS? ٤٠

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